Reducing HIV Growth to Zero

By Rowena Johnston, Ph.D., and Jeffrey Laurence, M.D.

March 18, 2010—Since three-drug highly active antiretroviral therapy (HAART) became available in the mid-1990s, scientists have been debating whether intensifying anti-HIV treatment might be able to slow virus growth rates even further than HAART, or even eradicate the virus from infected patients. Although the debate remains far from settled, new data from a group of scientists, including amfAR-funded researcher Dr. Sarah Palmer, are thought provoking.

Dr. Sarah Palmer

In a research article released online in Nature Medicine, Dr. Palmer, from the Swedish Institute for Infectious Disease Control, Dr. Mario Stevenson, chair of amfAR’s Scientific Advisory Committee, and a group of scientists from Spain studied patients whose virus levels were already well controlled on standard HAART. Although these patients had virus levels deemed “undetectable” by standard medical tests, more sensitive laboratory assays revealed each patient had extremely low but measurable amounts of virus in their blood. The researchers set out to determine whether adding one more drug to the treatment regimen—a recent addition to the treatment arsenal called raltegravir—would lower even further the ability of the virus to grow.

Measuring changes in growth rates in extremely low levels of virus is a considerable challenge. To do this, the researchers took advantage of the way in which raltegravir slows virus growth: the drug does not prevent the virus from entering a cell or from converting its genetic material into DNA, but it does prevent the virus’s DNA from being integrated into the patient’s DNA. They reasoned that if low-level viral growth was ongoing before the addition of raltegravir, then adding that drug would result in an accumulation of viral DNA inside infected cells, because the viral DNA would be unable to move on to the next step in the lifecycle, namely integrating into the cell’s DNA. Left out in the cold, this viral DNA assembles into 2-LTR circles, which Palmer and colleagues could find and measure utilizing a special test.

And find circles they did. Among 45 people who received raltegravir in addition to their standard drug regimen, 29 percent had an increase in 2-LTR circles inside infected cells. This suggests that although the patients’ virus levels had previously been extremely low, there may have been ongoing viral growth that was susceptible to further tamping down with raltegravir.

The fact that 71 percent of the subjects in this study did not show evidence of 2-LTR DNA when given raltegravir is good news. Most HIV positive individuals on HAART truly do not have active virus needing further attack. But these researchers suggest that for the one-third or so of patients who appear to have ongoing virus growth despite low levels of virus, intensifying treatment by adding raltegravir could be key to impeding the ability of the virus to grow and thereby maintain the viral reservoirs that stand in the way of HIV eradication.

Dr. Johnston is amfAR’s vice president and director of research and Dr. Laurence is senior scientific consultant.